Many eukaryotic cell types can polarize in response to an external gradient of chemoattractant. The ability to establish an internal compass that points in a precise direction is essential for yeast cells to mate, axons to find their way in the developing nervous system, and cells in the innate immune system to find and kill invading pathogens. Misregulation of cell migration is intimately involved in human disease, such as atherosclerosis and cancer metastasis. Understanding how biological networks dynamically control chemotactic responses is a key step towards developing targeted interventions in pathological conditions. Many of the components and interactions within neutrophil chemotaxis networks have been identified. However, it is not known how basic properties of chemotaxis emerge from detailed molecular descriptions of these networks. Our long term goals are to understand: 1) how dynamic polarization responses are generated by signaling networks;2) which properties of polarity are essential for guiding efficient motility;3) what general mechanisms are employed in diverse motile cells to regulate precise and efficient motility. Here, we propose to study how dynamic polarization and motility responses are generated by signaling networks in human neutrophils. Our specific aims are to: 1. Identify interactions within the chemotaxis network that control polarization dynamics;2. Model the polarization process;and 3. Identify key polarity phenotypes that are required for guiding efficient motility. PUBLIC HEALTH RELEVANCE: The ability of eukaryotic cells to polarize and migrate in response to external chemical cues is essential for diverse biological processes. While many biochemical components, interactions, and feedbacks within chemotaxis networks have been identified, a major challenge remains to understand how stereotyped polarization and motility responses emerge from these molecular details. Here, we propose to identify sources within human neutrophil signaling networks that control key response properties of chemotaxis.